Immune Stimulant Fails Randomized Test in Platinum-Resistant Ovarian Cancer

Charles Bankhead

June 2017, Vol 8, No 3 - Immunotherapy

National Harbor, MD—Platinum-resistant ovarian cancer also appeared resistant to the immunotherapeutic effects of the toll-like receptor 8 (TLR8) agonist motolimod as add-on to chemotherapy, according to results of a randomized trial.

Median overall survival (OS) with pegylated liposomal doxorubicin (PLD) and motolimod did not differ significantly from OS with PLD alone (18.1 vs 18.9 months). Median progression-free survival (PFS) was 4.8 months with motolimod and 5.2 months with PLD alone.

Investigators found no subgroups that derived significant benefit from the addition of motolimod, although a trend toward better survival was observed in patients who had injection-site reactions (ISRs), as reported at the 2017 Society of Gynecologic Oncology annual meeting.

“No associations were seen with TLR8 polymorphisms, BRCA1 or 2 or 69 other gene mutations, or with autoantibody markers,” said Bradley J. Monk, MD, FACOG, FACS, Professor, Department of Obstetrics and Gynecology, University of Arizona College of Medicine, Phoenix.

The rationale for motolimod’s clinical development came from preclinical evidence that the TLR8 agonist activates the immune system to induce an immune response. Additional preclinical studies showed that the addition of the drug enhanced tumor cell response to anthracyclines. A phase 1 trial provided additional support, demonstrating objective responses to the combination of motolimod and PLD in a majority of patients with advanced ovarian cancer.

The accumulation of evidence led to a phase 2 randomized trial sponsored by the Gynecologic Oncology Group/NRG Oncology. Investigators enrolled patients with recurrent platinum-resistant ovarian cancer, defined as relapse within 12 months of completing first- or second-line platinum-based chemotherapy.

Patients were randomized to PLD alone or in combination with motolimod, and treatment continued until disease progression. The primary end point was OS, and key secondary end points included investigator-assessed PFS and objective response.

Data analysis comprised 297 randomized patients. The primary analysis showed no significant difference in OS between treatment groups, and neither did PFS.

On the basis of prior clinical observations, investigators prespecified an analysis of the primary outcome by presence/absence of ISRs. Dr Monk reported that 108 patients treated with motolimod had ISRs, including 103 who had reactions within the landmark time frame of 56 days.

Comparison of patients with and without ISRs yielded a median OS of 19.8 months among patients with ISRs versus 13.3 months in patients without ISRs. The difference represented a 66% improvement in the survival hazard with ISRs, but the difference did not quite achieve statistical significance (P = .067).

The addition of motolimod did not add substantively to the safety profile of PLD alone, with the exception of ISRs, which occurred in 73.8% of the motolimod group and 41.2% of the placebo group.

“When added to PLD, motolimod does not improve overall survival, progression-free survival, or objective response rate in recurrent ovarian cancer,” said Dr Monk. “The combination was well-tolerated, with no synergistic or unexpected serious toxicity.”